Drug-free compositions and methods for diminishing peripheral inflammation and pain

Abstract

The present invention provides drug-free adaptable aggregate compositions, typically having a form of bilayer vesicles suspended in a polar, optionally thickened, fluid comprising different pharmaceutically acceptable excipients for use in or on a mammal for any medical indication, specifically for non-invasive treatment of local inflammation and the associated pain, in particular for use on the skin and underlying tissues, including muscles and/or superficial joints. Accompanying guidelines for selecting components to thereby optimizing the formulations are also provided.

1 . Composition for use in diminishing inflammation and/or pain in a mammal comprising adaptable vesicular aggregates, wherein the composition is pharmacological agent-free and preferably phospholipid-free. 
     
     
         2 . The composition for the use of  claim 1 ,
 wherein the relative molar concentrations of phospholipids, if any, compared with the concentration of all other aggregate-forming amphipats in the composition taken together is below 66 mol-%.   
     
     
         3 . The composition for the use of  claim 1 ,
 wherein the vesicularisation time of said aggregates in a polar fluid is at least 5-times shorter than the vesicularisation time of comparably suspended vesicles containing>90% pure soybean phosphatidylcholine liposomes.   
     
     
         4 . The composition for the use of  claim 1 ,
 wherein said aggregates have an average diameter of between 20 nm and 1 μm nm), and   wherein said amphipats occupy an average area per fluid chain in the bilayer of between about 0.35 nm 2  and about 0.55 nm 2 , preferably of 0.43±0.05 nm 2 .   
     
     
         5 . The composition for the use of  claim 1 , wherein said aggregates comprise:
 at least one amphipat characterised by a Hydrophilic-Lipophilic-Balance (HLB) number in the range of about 13.5>HLB>6.5, preferably in the range of about 12.5>HLB>7.5, and   wherein dispersion of the composition in a polar fluid yields bilayer vesicle aggregates capable of crossing pores smaller than the aggregate diameter without experiencing more than 50% fragmentation.   
     
     
         6 . Composition for use in diminishing inflammation and/or pain in a mammal comprising adaptable vesicular aggregates, wherein said aggregates comprise at least one amphipat,
 wherein the at least one amphipat contains at least one fluid hydrophobic segment with nC carbon atoms, and
 wherein the hydrophobic segment of the amphipat is directly or indirectly attached to at least one hydrophilic headgroup having about 5nC/24 to about 8.5nC/24 polarity units per hydrophobic segment, and optionally
 wherein the at least one amphipat can be supplemented with one or more additional amphipats, each having one or more polar headgroup, wherein the concentration of said additional amphipats, if any, is selected such that the average total of all polarity units on all amphipats is about 8.5 nC/24 polarity units per hydrophobic segment. 
 
   
     
     
         7 . The composition for the use of  claim 1 , wherein said aggregates comprise:
 one or more amphipats that can be dispersed into bilayer vesicles in a polar fluid, wherein said dispersion occurs at least two-fold faster when exposed to an external stress, such as a vigorous mechanical agitation, compared to a similarly concentrated and buffered reference aggregates composition made of at least 90% pure soybean phosphatidylcholine,   
     
     
         8 . The composition for the use according to  claims 1 ,
 wherein the composition further comprises non-ionic and/or zwitterionic and/or amphoteric amphipats, and   wherein the headgroup of a non-ionic amphipat is comprised of one or more hydrophilic segments attached to one or more fluid hydrophobic segments that together have a total of between at least 8 up to about 24 carbon atoms, and   wherein the total number of side-chains and/or side-groups and/or double bonds, if any, in the hydrophobic segments is between 1 and 3.   
     
     
         9 . The composition for the use of  claim 8 ,
 wherein the at least one hydrophilic segment is a pharmacologically acceptable polar group or a polymer thereof, selectable from:   a lower, linear or branched, alkyl chain alcohol that is hydroxylated on at least 50% of its carbons or   a sugar or an oligomer or lactone of said sugar, or   an amine oxide or its alkyl or dialkyl derivative, or   an amino or imino acid, or   a betaine or sulphobetaine, or   an aminoalkane sulphonic or sulphinic acid, an 1-amino-1-sulphosulphanylalkane, a dimethylammonio-1-alkanesulphonic, dimethylammonio-1-phosphonic, or dimethylammonio-1-acetic acid, a phospho-S,S-dimethyl mercapto short chain alkanol, or a secondary or ternary sulpho- or sulphono-short chain (poly)alkanolamine.   
     
     
         10 . Composition for use in diminishing inflammation and/or pain in a mammal, comprising adaptable vesicular aggregates, wherein said aggregates comprise at least one amphipat, and:
 the at least one amphipat has n fluid hydrophobic segments with a total of nC carbon atoms that are attached directly or indirectly to a zwitterionic or anionic headgroup of the at least one amphipat, said headgroup comprising an anionic phospho-, sulpho-, or arseno-moiety and optionally a cationic moiety, and   wherein the cationic moiety in the headgroup, if any, is a ternary or quaternary amine attached through a linker to the anionic moiety and   wherein the anionic moiety in the head group can be alkylated, coupled to a lower alkyl alcohol, an amino acid, a sugar, or to an oligomer thereof, and   wherein the at least one amphipat is optionally supplemented with a further amphipat, which is more polar if n=2 and less polar if n=1, and   wherein the overall polarity units count is between around 5nC/24 and about 8.5nC/24 per hydrophobic segment and the molar ratio of the first and the optional second amphipat, if more polar, exceeds 1/1.25.   
     
     
         11 . The composition for the use of  claim 10 ,
 wherein the first amphipat comprises two hydrophobic segments having a total of at least 20 carbon atoms and the zwitterionic headgroup is a phosphoalkanol-dimethylamine or sulphoalkanol-dimethylamine or a phosphoalkanol-trimethylamine or sulphoalkanol-trimethylamine, and   wherein the second amphipat is a surfactant with an area per chain exceeding the area per chain of the first amphipat, and   wherein the relative concentration of the first amphipat is selected such that the overall average area per chain in the mixed aggregate is 0.43±0.05 nm 2 .   
     
     
         12 . The composition for the use of  claim 1 , wherein the total dry mass of aggregate forming components is between about 1 wt.-% and 40 wt.-%. 
     
     
         13 . The composition for the use of  claim 1 , wherein the composition pH is between 3 and 9.5, and
 wherein for uncharged aggregates comprising ester-bonded molecules, the pH is between about 5 to about 8, and   wherein for the positively charged aggregates containing amphipats having hydrolysable headgroup-fatty-chain bonds, the pH is between about 3 and about 6, and   wherein for the negatively charged aggregates comprised of amphipats with hydrolysable headgroup-fatty-chain bonds the pH is between around 7 and around 9.5.   
     
     
         14 . The composition for the use of  claim 1 , wherein the aggregate composition has an average diameter between around 20 nm and around 1000 nm. 
     
     
         15 . The composition for the use of  claim 1 , wherein the aggregate composition is packaged into a multiple-dosing container. 
     
     
         16 . The composition for the use of  claim 1 , wherein the aggregate composition is administered on mammalian skin without an occlusive dressing in a quantity yielding a total amphipat mass per unit area of between 0.01 mg cm −2  and 2.5 mg cm −2 , and more specifically 0.15±0.075 mg cm −2  for superficial tissue treatment and about 1.5±0.75 mg cm −2  for deep tissue treatment. 
     
     
         17 . A composition for the use of  claim 16 , wherein the administration is repeated from 1 to 6 times daily 
     
     
         18 . A composition for the use of  claim 17 , wherein an overall treatment duration is between 1 and 3 weeks for acute indications, and between 4 and 156 weeks for chronic indications. 
     
     
         19 . The composition for the use of  claim 1 , wherein at least one additive is added to the aggregate composition and selected to act as a buffer and/or an antioxidant and/or a microbicide and/or a humectant and/or a fragrance and/or a co-solvent. 
     
     
         20 . A composition for the use of  claim 19 , wherein the at least one additive increases the average area per hydrophobic chain of the aggregate forming amphipats to thereby improve the aggregate adaptability. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled)